Martin M. Matzuk's research while affiliated with Baylor College of Medicine and other places
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Publications (565)
Background: Activating somatic ESR1 mutations Y537S and D538G occur more frequently in endocrine therapy-resistant metastatic breast cancer, which is associated with an aggressive phenotype and poor survival in breast cancer patients. These gain of function mutant receptors are constitutively active and allow resistance to first-line endocrine ther...
The discovery of monokinase-selective inhibitors for patients is challenging because the 500+ kinases encoded by the human genome share highly conserved catalytic domains. Until now, no selective inhibitors unique for a single transforming growth factor β (TGFβ) family transmembrane receptor kinase, including bone morphogenetic protein receptor typ...
Background:
Adenosine Deaminase Domain Containing 2 (ADAD2) is a testis-specific protein composed of a double-stranded RNA binding domain and a non-catalytic adenosine deaminase domain. A recent study showed that ADAD2 is indispensable for the male reproduction in mice. However, the detailed functions of ADAD2 remain elusive.
Objectives:
This st...
Ovarian cancer (OC) is one of the deadliest cancers affecting the female reproductive system. It may present little or no symptoms at the early stages, and typically unspecific symptoms at later stages. High-grade serous ovarian cancer (HGSC) is the subtype responsible for most ovarian cancer deaths. However, very little is known about the metaboli...
The cochlea’s ability to discriminate sound frequencies is facilitated by a special topography along its longitudinal axis known as tonotopy. Auditory hair cells located at the base of the cochlea respond to high-frequency sounds, whereas hair cells at the apex respond to lower frequencies. Gradual changes in morphological and physiological feature...
Characterization of protein–protein interactions (PPI) is a key to understanding the functions of proteins of interest. Recently developed proximity-dependent biotin identification (BioID) has been actively investigated as an alternative PPI mapping method because of its usefulness in uncovering transient PPI. Here, as an example of proximity label...
Background:
Lactate dehydrogenase C (LDHC) is specifically expressed in male germ cells and plays critical roles in glycolysis. Glycolysis is required to supply energy for sperm motility. Previous studies showed that Ldhc knockout mice exhibit impaired sperm motility.
Objectives:
We established human LDHC knock-in (hLDHC KI) mice and examined wh...
Muscle regeneration requires the coordination of muscle stem cells, mesenchymal fibro-adipogenic progenitors (FAPs), and macrophages. How macrophages regulate the paracrine secretion of FAPs during the recovery process remains elusive. Herein, we systemically investigated the communication between CD206⁺ M2-like macrophages and FAPs during the reco...
Background:
Each year, infertility affects 15% of couples worldwide, with 50% of cases attributed to men. Globozoospermia is an uncommon cause of male factor infertility, characterized by defects in sperm acrosome formation, leading to round-headed spermatozoa.
Objective:
We generated phosducin-like 2 (PDCL2) knockout (-/-) mice to investigate t...
Background:
A safe, effective, and reversible nonhormonal male contraceptive drug is greatly needed for male contraception as well as for circumventing the side effects of female hormonal contraceptives. Phosducin-like 2 (PDCL2) is a testis-specific phosphoprotein in mice and humans. We recently found that male PDCL2 knockout mice are sterile due...
Background:
The importance of phosphorylation in sperm during spermatogenesis has not been pursued extensively. Testis-specific serine kinase 3 (Tssk3) is a conserved gene, but TSSK3 kinase functions and phosphorylation substrates of TSSK3 are not known.
Objective:
The goals of our studies were to understand the mechanism of action of TSSK3.
Ma...
Meiosis has a principal role in sexual reproduction to generate haploid gametes in both sexes. During meiosis, the cell nucleus hosts a dynamic environment where some genes are transcriptionally activated, and some are inactivated at the same time. This becomes possible through subnuclear compartmentalization. The sex body, sequestering X and Y chr...
Background
Ubiquitination is a post-translational modification required for a number of physiological functions regulating protein homeostasis, such as protein degradation. The endoplasmic reticulum (ER) quality control system recognizes and degrades proteins no longer needed in the ER through the ubiquitin–proteasome pathway. E2 and E3 enzymes con...
Significance
BET bromodomain inhibition is therapeutic in multiple diseases; however, pan-BET inhibitors have induced significant myelosuppression and gastrointestinal toxicity, perhaps due to inhibition of both tandem bromodomains (BD) of all BET family members. However, selective inhibition of just the first BD (BD1) phenocopies pan-BET inhibitor...
Duloxetine (DLX) is a dual serotonin and norepinephrine reuptake inhibitor for the treatment of major depressive disorder, mainly metabolized by CYP1A2 and CYP2D6 in human. Despite DLX has a good tolerance, serious adverse events (e.g., liver injury) have been reported in rare cases. The role of DLX metabolism in its toxicity remains unclear. Here,...
Despite the advances in β-lactamase inhibitor development, limited options exist for the class D carbapenemase known as OXA-48. OXA-48 is one of the most prevalent carbapenemases in carbapenem-resistant Enterobacteriaceae infections and is not susceptible to most available β-lactamase inhibitors. Here, we screened various low-molecular-weight compo...
Duloxetine (DLX) is a dual serotonin and norepinephrine reuptake inhibitor, widely used for the treatment of major depressive disorder. Although DLX has shown good efficacy and safety, serious adverse effects (e.g., liver injury) have been reported. The mechanisms associated with DLX-induced toxicity remain elusive. Drug metabolism plays critical r...
Significance
Adult neurogenesis, which is known to be a heritable trait, is thought to be involved in learning, stress-related anxiety, and antidepressant action. In this study, we map genes influencing adult neurogenesis and identify a candidate gene, follistatin ( Fst ) for further study. By utilizing a brain-specific knockout and viral vector-me...
Significance
SARS-CoV-2 has had a crippling impact on human life globally. Vaccine development has been used as a first-line strategy for COVID-19 prevention and mitigation; however, small-molecule drugs are still vitally needed to extend treatment options. Traditional screening methods for identifying biologically active small molecules are sluggi...
Infertility afflicts up to 15% of couples globally each year with men a contributing factor in half of these cases. Globozoospermia is a rare condition found in infertile men that is characterized by defective acrosome biogenesis leading to the production of round shaped sperm. Here, we report a novel gene, Fam209 (Family with sequence similarity 2...
Here we report the successful construction of a novel, stereochemically diverse DNA-Encoded Chemical Library (DECL) by utilizing 24 enantiomerically pure trifunctional 2, 6- di-substituted piperazines as central cores. We introduce the concept of positional diversity by placing the DNA attachment at either of two possible sites on the piperazine sc...
Significance
Maintenance of skeletal muscle and bone is regulated by key signaling proteins belonging to the transforming growth factor family. Here, we present genetic studies in mice showing that follistatin, which normally blocks the activities of these proteins, acts locally in an exquisitely dose-dependent manner to control muscle and bone gro...
During early pregnancy in the mouse, nidatory estrogen (E2) stimulates endometrial receptivity by activating a network of signaling pathways that is not yet fully characterized. Here, we report that bone morphogenetic proteins (BMPs) control endometrial receptivity via a conserved activin receptor type 2 A (ACVR2A) and SMAD1/5 signaling pathway. Mi...
Recent evidence indicates that niclosamide is an anti-cancer compound that is able to inhibit several signaling pathways. While niclosamide has previously been identified by high-throughput screening platforms as a potential effective compound against several cancer types, no direct binding interactions with distinct biological molecule(s) has been...
Proteomic signatures associated with clinical measures of more aggressive cancers could yield molecular clues as to disease drivers. Here, utilizing the Clinical Proteomic Tumor Analysis Consortium (CPTAC) mass-spectrometry-based proteomics datasets, we defined differentially expressed proteins and mRNAs associated with higher grade or higher stage...
Significance
There is no nonhormonal contraceptive pill for men, although hundreds of genes have been identified to play roles during spermatogenesis and fertilization in the male reproductive tract. To address the absence of contraceptive drugs for men, we established a DNA-encoded chemistry technology (DEC-Tec) platform. Our drug discovery campai...
Significance
Although formation of the mitochondrial sheath is a critical process in the formation of mature spermatozoa, the molecular mechanisms involved in mitochondrial sheath genesis remain unclear. Using gene-manipulated mice, we discovered that ARMC12 regulates spatiotemporal “sperm mitochondrial dynamics” during mitochondrial sheath formati...
A zinc bromide-catalyzed synthesis of 5-substituted tetrazoles via DNA-conjugated nitriles using sodium azide has been developed. The protocol offered moderate to excellent yields of tetrazoles with a broad range of substrates, including a variety of functionalized aromatic, heterocyclic, and aliphatic nitriles. In addition, the electronic effect w...
Sperm cooperation has been observed in multiple species, yet its existence and benefit for reproductive success in mammals remains underexplored. Here, combining tissue-clearing with deep three-dimensional imaging, we demonstrate that postcopulatory mouse sperm congregate into unidirectional sperm cooperative clusters at the utero-tubal junction (U...
Sperm cooperation has been observed in multiple species, yet its existence and benefit for reproductive success in mammals remains underexplored. Here, combining tissue-clearing with deep three-dimensional imaging, we demonstrate that postcopulatory mouse sperm congregate into unidirectional sperm cooperative clusters at the utero-tubal junction (U...
Peptide drug discovery has shown a resurgence since 2000, bringing 28 non-insulin therapeutics to the market compared to 56 since its first peptide drug, insulin, in 1923. While the main method of discovery has been biological display—phage, mRNA, and ribosome—the synthetic limitations of biological systems has restricted the depth of exploration o...
Background:
The development of a safe, effective, reversible, non-hormonal contraceptive method for men has been an ongoing effort for the past few decades. However, despite significant progress on elucidating the function of key proteins involved in reproduction, understanding male reproductive physiology is limited by incomplete information on t...
The flagellum is essential for sperm motility and fertilization in vivo. The axoneme is the main component of the flagella, extending through its entire length. An axoneme is comprised of two central microtubules surrounded by nine doublets, the nexin-dynein regulatory complex, radial spokes, and dynein arms. Failure to properly assemble components...
Significance
To rapidly identify small-molecule lead compounds to target healthcare-associated proteases, we constructed a unique 9.8-million-membered protease-focused DNA-encoded chemical library. Affinity selection of this library with a healthcare-relevant protease (i.e., thrombin, a key protein necessary for blood coagulation) revealed potent i...
Local control of sperm maturation
Newly produced spermatozoa within the testis do not have fertilizing ability but become fully functional when they mature in the epididymis. The development of the epididymis itself is dependent on testicular factors arriving via luminal flow. Improper signaling between the testis and epididymis is hypothesized to...
Developing a safe and effective male contraceptive remains a challenge in the field of medical science. Molecules that selectively target the male reproductive tract and whose targets are indispensable for male reproductive function serve among the best candidates for a novel non-hormonal male contraceptive method. To determine the function of thes...
As the world population continues to increase to unsustainable levels, the importance of birth control and the development of new contraceptives are emerging. To date, male contraceptive options have been lagging behind those available to women, and those few options available are not satisfactory to everyone. To solve this problem, we have been se...
CRISPR/Cas9-based genome editing in mice uncovers 13 testis-or epididymis-enriched genes individually dispensable for male reproduction Running title: Genome editing reveals dispensable testis-and epididymis-enriched genes Summary sentence: Thirteen testis-or epididymis-enriched genes are individually dispensable for male fertility based on phenoty...
Family with sequence similarity 170 members A and B (FAM170A and FAM170B) are two testis-specific, paralogous proteins that share 31% amino acid identity and are conserved throughout mammals. While in vitro experiments in previous literature suggested that FAM170B, an acrosome-localized protein, plays a role in the mouse sperm acrosome reaction and...
Significance
The sperm−oocyte fusion step is important to transport the male genome into oocytes. So far, IZUMO1 and FIMP have been identified as fusion-related proteins in spermatozoa, but the molecular mechanisms underpinning sperm−oocyte fusion and all of the proteins required for this essential process remain unclear. In this study, using CRISP...
Spermatogenesis is a complex developmental process that involves the proliferation of diploid cells, meiotic division, and haploid differentiation. Many genes are shown to be essential for male fertility using knockout (KO) mice; however, there still remain genes to be analyzed to elucidate their molecular mechanism and their roles in spermatogenes...
Spermatozoa are produced in the testis but gain their fertilizing ability during epididymal migration. This necessary step in sperm maturation includes post-translational modification of sperm membrane proteins that includes protein processing by proteases. However, the molecular mechanism underpinning this epididymal sperm maturation remains unkno...
Mammalian spermatozoa are produced in the testis through spermatogenesis and matured in the epididymis to acquire fertilizing ability. Spermatozoa are ejaculated and migrate from the uterus to the oviducts to fuse with oocytes. Although over 2,000 genes are expressed abundantly in mouse testes, the genes responsible for male fertility are not yet f...
Globozoospermia (sperm with an abnormally round head shape) and asthenozoospermia (defective sperm motility) are known causes of male infertility in human patients. Despite many studies, the molecular details of the globozoospermia etiology are still poorly understood. Serine-rich single pass membrane protein 1 (Ssmem1) is a conserved testis-specif...
Significance
As the human body is composed of 60 trillion cells that originate from a fertilized egg, sperm–oocyte fusion is the initial event of our life. Few sperm–oocyte fusion factors have been unveiled to date, and only IZUMO1 has been identified as a sperm-specific fusion-mediating protein. Here, we identified the testis-specific 4930451I11Ri...
JQ1 is a small-molecule inhibitor of the bromodomain and extra terminal (BET) protein family that potently inhibits the bromodomain testis-specific protein (BRDT), which is essential for spermatogenesis. JQ1 treatment produces a reversible contraceptive effect by targeting the activity of BRDT in mouse male germ cells, validating BRDT as a male con...
Bacterial resistance to β-lactam antibiotics is largely mediated by β-lactamases, which catalyze the hydrolysis of these drugs and continue to emerge in response to antibiotic use. β-Lactamases that hydrolyze the last resort carbapenem class of β-lactam antibiotics (carbapenemases) are a growing global health threat. Inhibitors have been developed...
Receptor accessory protein 6 (REEP6) is a member of the REEP/Ypt-interacting protein (Yip) family that we recently identified as essential for normal endoplasmic reticulum (ER) homeostasis and protein trafficking in the retina of mice and humans. Interestingly, in addition to the loss of REEP6 in our knockout (KO) mouse model recapitulating the ret...
DNA-encoded chemical library (DECL) screens are a rapid and economical tool to identify chemical starting points for drug discovery. As a robust transformation for drug discovery, palladium-catalyzed C–N coupling is a valuable synthetic method for the construction of DECL chemical matter—however currently disclosed methods have only been demonstrat...
Reaction heterogeneity, poor pH control, and catalyst decomposition in the ring-closing metathesis (RCM) of DNA–chemical conjugates leads to poor yields of the cyclized products. Herein we address these issues with a RCM reaction sys-tem that includes a novel aqueous solvent combination to enable reaction homogeneity, an acidic buffer system which...
The t-complex is defined as naturally occurring variants of the proximal third of mouse chromosome 17 and has been studied by mouse geneticists for decades. This region contains many genes involved in processes from embryogenesis to sperm function. One such gene, t-complex protein 11 (Tcp11), was identified as a testis-specific gene whose protein i...
Significance
While the emergence of gene modification technologies has produced major discoveries in biomedical sciences, the recent development of the CRISPR/Cas9 system has dramatically altered the trajectory of phenotypic analysis in animal models. In this study, we identified male-specific gene clusters ( Cst and Pate ) and family genes ( Gdpd...
High throughput transcriptomics and proteomics approaches have recently identified a large number of germ cell-specific genes with many that remain to be studied through functional genetics approaches. Serine proteases (PRSS) constitute nearly one-third of all proteases, and, in our bioinformatics screens, we identified many that are testis-specifi...
A strategy for DNA-compatible, palladium-catalyzed hydroxycarbonylation of (hetero)aryl halides on DNA-chemical con-jugates has been developed. This method generally provided the corresponding carboxylic acids in moderate to very good conversions for (hetero)aryl iodides and bromides, and in poor to moderate conversions for (hetero)aryl chlorides....
TGFβ family ligands, which include the TGFβs, BMPs, and activins, signal by forming a ternary complex with type I and type II receptors. For TGFβs and BMPs, structures of ternary complexes have revealed differences in receptor assembly. However, structural information for how activins assemble a ternary receptor complex is lacking. We report the st...
More than 1,000 genes are predicted to be predominantly expressed in mouse testis, yet many of them remain unstudied in terms of their roles in spermatogenesis and sperm function and their essentiality in male reproduction. Since individually indispensable factors can provide important implications for the diagnosis of genetically-related idiopathi...
A multistep protocol for the synthesis of 3,5-disubstituted 1,2,4-oxadiazoles on DNA-chemical conjugates has been developed. A set of six DNA-connected aryl nitriles were converted to corresponding amidoximes with hydroxylamine followed by the O-acylation with a series of aryl and aliphatic carboxylic acids. After cyclodehydration of the O-acyl ami...
Background
Spermatozoa become competent for fertilization during transit through the epididymis. As spermatozoa from the proximal caudal epididymis can fertilize eggs, proteins from the caput and corpus epididymis are required for sperm maturation.
Objectives
Microarray analysis identified that more than 17,000 genes are expressed in the epididymi...
A hypodiboric acid system for the reduction of nitro groups on DNA-chemical conjugates has been developed. This transformation provided good to excellent yields of the reduced amine product for a variety of functionalized aromatic, heterocyclic, and aliphatic nitro compounds. DNA tolerance to reaction conditions, extension to decigram scale reducti...
DNA-encoded chemical libraries (DELs) provide a high-throughput and cost-effective route for screening billions of unique molecules for binding affinity for diverse protein targets. Identifying candidate compounds from these libraries involves affinity selection, DNA sequencing, and measuring enrichment in a sample pool of DNA barcodes. Successful...
Significance
The rising incidence of endometrial cancer in the United States and worldwide can be partially attributed to elevated rates of obesity in the population. Although hysterectomy is an effective treatment for early endometrial cancer, medical interventions are required in advanced cases with metastatic disease or for women wishing to pres...
SMAD2 and SMAD3 are downstream proteins in the transforming growth factor-β (TGF β) signaling pathway that translocate signals from the cell membrane to the nucleus, bind DNA, and control the expression of target genes. While SMAD2/3 have important roles in the ovary, we do not fully understand the roles of SMAD2/3 in the uterus and their implicati...
Throughout the male reproductive lifespan, spermatogonial stem cells (SSCs) produce committed progenitors that proliferate and then remain physically connected in growing clones via short cylindrical intercellular bridges (ICBs). These ICBs, which enlarge in meiotic spermatocytes, have been demonstrated to provide a conduit for postmeiotic haploid...
Background:
Bulk tumor tissue samples are used for generating gene expression profiles in most research studies, making it difficult to decipher the stroma-cancer crosstalk networks. In the present study, we describe the use of microdissected transcriptome profiles for the identification of cancer-stroma crosstalk networks with prognostic value, w...
A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
The embryonic development and adult function of the mammalian reproductive tract is greatly influenced by multiple conserved growth factor signaling pathways. These include transforming growth factor-β (TGF-β), wingless-type MMTV integration site (WNT), Hedgehog, epidermal growth factor (EGF), insulin-like growth factor (IGF), phosphatidylinositol...
